In vivo prostate cancer detection and grading using restriction spectrum imaging-MRI.

BACKGROUND: Magnetic resonance imaging (MRI) is emerging as a robust, noninvasive method for detecting and characterizing prostate cancer (PCa), but limitations remain in its ability to distinguish cancerous from non-cancerous tissue. We evaluated the performance of a novel MRI technique, restriction spectrum imaging (RSI-MRI), to quantitatively detect and grade PCa compared with current standard-of-care MRI. METHODS: In a retrospective evaluation of 33 patients with biopsy-proven PCa who underwent RSI-MRI and standard MRI before radical prostatectomy, receiver-operating characteristic (ROC) curves were performed for RSI-MRI and each quantitative MRI term, with area under the ROC curve (AUC) used to compare each term's ability to differentiate between PCa and normal prostate. Spearman rank-order correlations were performed to assess each term's ability to predict PCa grade in the radical prostatectomy specimens. RESULTS: RSI-MRI demonstrated superior differentiation of PCa from normal tissue, with AUC of 0.94 and 0.85 for RSI-MRI and conventional diffusion MRI, respectively (P=0.04). RSI-MRI also demonstrated superior performance in predicting PCa aggressiveness, with Spearman rank-order correlation coefficients of 0.53 (P=0.002) and -0.42 (P=0.01) for RSI-MRI and conventional diffusion MRI, respectively, with tumor grade. CONCLUSIONS: RSI-MRI significantly improves upon current noninvasive PCa imaging and may potentially enhance its diagnosis and characterization.

Novel technique for characterizing prostate cancer utilizing MRI restriction spectrum imaging: proof of principle and initial clinical experience with extraprostatic extension.

BACKGROUND: Standard magnetic resonance imaging (MRI) of the prostate lacks sensitivity in the diagnosis and staging of prostate cancer (PCa). To improve the operating characteristics of prostate MRI in the detection and characterization of PCa, we developed a novel, enhanced MRI diffusion technique using restriction spectrum imaging (RSI-MRI). METHODS: We compared the efficacy of our novel RSI-MRI technique with standard MRI for detecting extraprostatic extension (EPE) among 28 PCa patients who underwent MRI and RSI-MRI prior to radical prostatectomy, 10 with histologically proven pT3 disease. RSI cellularity maps isolating the restricted isotropic water fraction were reconstructed based on all b-values and then standardized across the sample with z-score maps. Distortion correction of the RSI maps was performed using the alternating phase-encode technique. RESULTS: 27 patients were evaluated, excluding one patient where distortion could not be performed. Preoperative standard MRI correctly identified extraprostatic the extension in two of the nine pT3 (22%) patients, whereas RSI-MRI identified EPE in eight of nine (89%) patients. RSI-MRI correctly identified pT2 disease in the remaining 18 patients. CONCLUSIONS: In this proof of principle study, we conclude that our novel RSI-MRI technology is feasible and shows promise for substantially improving PCa imaging. Further translational studies of prostate RSI-MRI in the diagnosis and staging of PCa are indicated.

Lifestyle and health factors associated with progressing and remitting trajectories of untreated lower urinary tract symptoms among elderly men.

BACKGROUND: Knowledge of factors associated with the course of lower urinary tract symptoms (LUTS) before treatment is needed to inform preventive interventions. In a prospective study of elderly men untreated for LUTS, we identified factors associated with symptom progression and remission. METHODS: In community-dwelling US men aged ≥65 years, the American Urological Association Symptom Index (AUA-SI) was repeated four times, once at baseline (2000-2002) and then every 2 years thereafter. Analyses included 1740 men with all four AUA-SI assessments, who remained free from diagnosed prostate cancer, and who reported no treatment for LUTS or BPH during follow-up that averaged 6.9 (±0.4) years. LUTS change was determined with group-based trajectory modelingof the repeated AUA-SI measures. Multivariable logistic regression was then used to determine the baseline factors associated with progressing compared with stable trajectories, and with remitting compared with progressing trajectories. Lifestyle, body mass index (BMI) (kg/m(2)), mobility, mental health (Short-Form 12), medical history and prescription medications were considered for selection. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for variables in each model. RESULTS: We identified 10 AUA-SI trajectories: 4 stable (1277 men, 73%), three progressing (345 men, 20%), two remitting (98 men, 6%) and one mixed (20 men, 1%). Men in progressing compared with stable trajectories were more likely to have mobility limitations (OR=2.0, 95% CI: 1.0-3.8), poor mental health (OR=1.9, 95% CI: 1.1-3.4), BMI≥25.0 kg m(-2) (OR=1.7, 95% CI: 1.0-2.8), hypertension (OR=1.5, 95% CI: 1.0-2.4) and back pain (OR=1.5, 95% CI: 1.0-2.4). Men in remitting compared with progressing trajectories more often used central nervous system medications (OR=2.3, 95% CI: 1.1-4.9) and less often had a history of problem drinking (OR=0.4, 95% CI: 0.2-0.9). CONCLUSIONS: Several non-urological lifestyle and health factors were independently associated with risk of LUTS progression in older men.

Robotic-assisted simple prostatectomy: a systematic review and report of a single institution case series.

Open simple prostatectomy (OSP) is an effective treatment for patients with symptomatic BPH and larger volume prostates; however, it is associated with substantial risks of bleeding, transfusion and prolonged hospital length of stay (LOS). Robotic-assisted simple prostatectomy (RASP) potentially offers improved perioperative outcomes for these patients. We systematically reviewed published data on RASP outcomes and analyzed our experience at the University of California San Diego (UCSD). We identified eight published studies, all non-comparative case series (Level 3 evidence), reporting a total of 109 RASP cases from 2008 to 2012. Indications included acute urinary retention (n=48), persistent obstructive symptoms (n=51), failure of medical management (n=9) and recurrent urinary tract infections (n=2). The mean ages ranged from 65 to 77 years. More than 75% of the studies reported a mean LOS <3 days and a transfusion prevalence of 0%. The mean resected prostate weights ranged from 51 to 301 g. For UCSD, indications for surgery included urinary retention (n=11) and failure of medical management (n=5). The mean age was 68 years, transfusion prevalence 0%, mean resected prostate weight 94 g and mean LOS 1 day. All nine series observed substantial postoperative improvements in urinary symptoms and retention. These data suggest that RASP is a safe and efficacious treatment for BPH in select patients with larger prostates. Although LOS and transfusion prevalence for RASP are markedly lower than the published OSP series, comparative studies are needed to verify these results.

The incidence of acute urinary retention secondary to BPH is increasing among California men.

BACKGROUND: Current epidemiological patterns of adverse events of clinical BPH remain unclear. We investigated trends in acute urinary retention (AUR) associated with BPH in a large, population-based cohort. METHODS: We utilized the California Office of Statewide Health Planning and Development Database to examine 3 724 016 emergency room (ER) visits in California among men aged  50 years from 2007 to 2010. Outcomes included AUR for which BPH was the primary diagnosis, AUR for which BPH was a secondary diagnosis and urethral catheterization for AUR. We generated adjusted odds ratios (ORadj) using multivariate logistic regression to determine longitudinal trends. RESULTS: A total of 17 023 men presented with a diagnosis of BPH-associated AUR, the unadjusted incidence of which increased from 4.00 per 1000 ER visits in 2007 to 5.23 per 1000 ER visits in 2010 (P<0.001). In adjusted analyses, primary AUR (ORadj=1.25; 95% confidence interval (CI), 1.19-1.32; P<0.001) and secondary AUR (ORadj=1.80; 95% CI, 1.62-2.00; P<0.001) increased 25% and 80%, respectively. Urethral catheterization for primary (ORadj=1.30; 95% CI, 1.22-1.39; P<0.001) and secondary (ORadj=1.82; 95% CI, 1.57-2.11; P<0.001) AUR increased 30% and 82%, respectively. Asian race (P<0.001), Hispanic race (P<0.001) and commercial insurance (P<0.001) were associated with significantly increased risks of AUR and urethral catheterization. CONCLUSIONS: Between 2007 and 2010, the observed incidence of BPH-associated AUR increased substantially in a large and ethnically diverse male population of the United States.

Prostate atypia: clinical and pathological variables associated with cancer diagnosis on repeat biopsy.

The clinical significance of atypical glands suspicious for malignancy (atypia) on prostate biopsy is unclear. We studied a cohort of 139 patients with atypia who underwent repeat prostate biopsy. We analyzed clinical and pathological variables that may be associated with cancer on repeat biopsy. Cancer was diagnosed in 41 (29%) of patients with atypia: 26 of 41 (66%) were Gleason 6, 20% were Gleason 7 and 7% were Gleason 8 (Gleason < 6 not reported). There were no significant associations of age, race, family history, PSA, PSA density (PSAd), number of previous biopsies or time to repeat biopsy with cancer diagnosis. In multivariate regression, histological inflammation was associated with an 85% decreased probability of cancer on repeat biopsy (odds ratio; OR 0.15; 95% confidence interval; CI 0.04-0.57; P=0.04). Radical prostatectomy was performed in 14 of 41 (34%) patients with cancer; 6 (43%) were Gleason sum ≥7, 3 (21%) were pT3a and 1 (7%) had lymph node metastases. In conclusion, inflammation was independently associated with a significantly decreased risk of cancer on repeat biopsy. However, some patients with initial atypia have higher-risk prostate cancer. Additional studies are needed to elucidate these associations.

Target localization and toxicity in dose-escalated prostate radiotherapy with image-guided approach using daily planar kilovoltage imaging.

Dose escalation with intensity-modulated radiation therapy (IMRT) for carcinoma of the prostate has augmented the need for accurate prostate localization prior to dose delivery. Daily planar kilovoltage (kV) imaging is a low-dose image-guidance technique that is prevalent among radiation oncologists. However, clinical outcomes evaluating the benefit of daily kV imaging are lacking. The purpose of this study was to report our clinical experience, including prostate motion and gastrointestinal (GI) and genitourinary (GU) toxicities, using this modality. A retrospective analysis of 100 patients treated consecutively between December 2005 and March 2008 with definitive external beam IMRT for T1c-T4 disease were included in this analysis. Prescription doses ranged from 74-78 Gy (median, 76) in 2 Gy fractions and were delivered following daily prostate localization using on-board kV imaging (OBI) to localize gold seed fiducial markers within the prostate. Acute and late toxicities were graded as per the NCI CTCAEv3.0. The median follow-up was 22 months. The magnitude and direction of prostate displacement and daily shifts in three axes are reported. Of note, 9.1% and 12.9% of prostate displacements were ≥ 5 mm in the anterior-posterior and superior-inferior directions, respectively. Acute grade 2 GI and GU events occurred in 11% and 39% of patients, respectively, however no grade 3 or higher acute GI or GU events were observed. Regarding late toxicity, 2% and 17% of patients developed grade 2 toxicities, and similarly no grade 3 or higher events had occurred by last follow-up. Thus, kV imaging detected a substantial amount of inter-fractional displacement and may help reduce toxicity profiles, especially high grade events, by improving the accuracy of dose delivery.

Lifestyle factors, benign prostatic hyperplasia, and lower urinary tract symptoms.

PURPOSE OF REVIEW: Although age, genetics, and sex steroid hormones play prominent roles in the cause of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), recent epidemiological studies suggest that modifiable lifestyle factors also contribute substantially to the pathogenesis of these conditions. RECENT FINDINGS: Lifestyle and metabolic factors associated with significantly increased risks of benign prostatic hyperplasia and lower urinary tract symptoms include obesity, diabetes, and meat and fat consumption. Factors associated with decreased risks include physical activity, moderate alcohol intake, and vegetable consumption. Factors for which no clear risk patterns have emerged include lipids and smoking. Randomized clinical trials of lifestyle alterations - such as weight loss, exercise, and diet - for the prevention or treatment of benign prostatic hyperplasia and lower urinary tract symptoms have yet to be performed. SUMMARY: Lifestyle factors present a novel opportunity for the prevention and treatment of benign prostatic hyperplasia and lower urinary tract symptoms. Although clinical trials of lifestyle modifications have not yet been undertaken, promotion of healthy lifestyle alternatives within the context of standard benign prostatic hyperplasia and lower urinary tract symptoms treatment algorithms is potentially beneficial.

Robot-assisted laparoscopic radical prostatectomy in men with human immunodeficiency virus.

The aim of this study is to evaluate the outcomes of robot-assisted laparoscopic prostatectomy (RALP) in prostate cancer (PCa) patients with human immunodeficiency virus (HIV). This is a prospective cohort study of HIV patients undergoing RALP, comparing the demographics, tumor characteristics, complications, and short-term oncological outcomes of HIV-positive men to HIV-negative men using univariate (χ(2), Mann-Whitney test) and multivariable (logistic regression) analyses. From 2007 to 2010, 298 men underwent RALP, 8 of whom were known to be HIV positive. Preoperatively, all eight were taking highly active antiretroviral therapy (HAART) and had undetectable viral loads (<50); mean CD4 count was 634 cells per mm(3). HIV-positive men were younger (54 versus 62 years, P=0.010) and less likely to be white (P=0.007). There were no significant differences between groups with respect to clinical staging, pathological and oncological outcomes or most complication rates. However, the prevalence of perioperative transfusions (P=0.031) and ileus (P=0.021) were higher in HIV-positive patients. HIV remained significantly associated with risk of transfusion after adjustment for age, race, Gleason sum and clinical T stage (P=0.002). After a median of 2.6 (range 0.03-19.2) months of follow-up, PSA remained undetectable in all eight HIV patients. These data suggest that RALP is safe for, and demonstrates short-term oncological efficacy in, HIV-positive patients with PCa.

Prostate cancer prevention: concepts and clinical recommendations.

Prevention is an important strategy for limiting prostate cancer morbidity and mortality. Two major types of prevention are primary (reduction of incident cases) and tertiary (inhibition of disease progression and recurrence). Pharmacological and dietary interventions have potential functions in both the primary and tertiary prevention of prostate cancer. Five-α reductase inhibitors (5-ARIs) reduce the incidence of prostate cancer in both general and higher-risk populations and are currently under study for tertiary prevention in active surveillance and biochemical recurrence patients. Selenium, vitamin E, and vitamin C do not prevent incident prostate cancer in the general population; however, other promising diet-based interventions are currently under study for tertiary prevention. We recommend consideration of 5-ARIs for prostate cancer prevention in (1) asymptomatic men with a PSA ≤ 3.0 ng ml(-1) who are undergoing or anticipate undergoing PSA screening for early detection of prostate cancer and (2) asymptomatic men with PSA ≥ 2.5 and ≤ 10 ng ml(-1) and an earlier prostate biopsy negative for cancer. Men should be informed of the potential risks of 5-ARI therapy. Currently, there is neither clinical evidence to support the use of 5-ARIs for tertiary prevention in active surveillance or biochemical recurrence populations, nor micronutrients for prostate cancer prevention of any type.

Prevalence of benign microscopic hematuria among women with interstitial cystitis: implications for evaluation of genitourinary malignancy.

OBJECTIVES: To assess the prevalence of benign microscopic hematuria among a cohort of women with clinical interstitial cystitis (IC). METHODS: A total of 100 women were prospectively assessed for microscopic hematuria with postvoid sterile catheterization. The evaluation for all patients included urine culture, potassium sensitivity test (PST), cystoscopy with hydrodistension under general anesthesia, and symptom assessment with the Pelvic Pain and Urgency/Frequency (PUF) questionnaire. RESULTS: The mean age +/- SD was 37 +/- 15 years, with no difference noted in those with or without microscopic hematuria (P = 0.71). Microscopic hematuria was present in 24 (24%) of the 100 women. No patient had gross hematuria, positive urine culture, or cystoscopic findings suspicious for malignancy. The mean PUF score was 17 +/- 6. The PST was positive in 92 (92%) of 100 women, and 8 patients had only cystoscopic findings diagnostic of IC. The likelihood of a positive PST or positive cystoscopic findings among patients with microscopic hematuria was similar to that of patients without microscopic hematuria. The PST results correlated with the cystoscopic findings (P < 0.001). Of 36 patients with positive cystoscopic findings, 28 (78%) had a positive PST, and 28 (30%) of 92 with a positive PST had positive cystoscopy findings. CONCLUSIONS: In this cohort of women with IC, the prevalence of benign microscopic hematuria was 24%. These data suggest that in women at low risk of genitourinary malignancy who have clinical IC, microscopic hematuria may be an incidental finding.

p63 protein expression is rare in prostate adenocarcinoma: implications for cancer diagnosis and carcinogenesis.

OBJECTIVES: To examine the expression of the p63 protein in normal, preneoplastic, and neoplastic human prostatic tissue. The p63 gene, a member of the p53 gene family, is expressed in the basal epithelial cells of multiple organs. Irregularities in p63 expression have been associated with epithelial carcinogenesis. METHODS: We performed immunohistochemistry with an anti-p63 antibody on specimens from radical prostatectomies, prostate needle biopsies, and metastatic prostate adenocarcinoma. We analyzed p63 expression in regions of normal prostate, benign prostatic hyperplasia, proliferative inflammatory atrophy (PIA), high-grade intraepithelial neoplasia, and adenocarcinoma. RESULTS: Basal epithelial cells in normal, benign prostatic hyperplasia, and high-grade intraepithelial neoplasia tissue stained intensely for the p63 polypeptide, but the vast majority of adenocarcinoma specimens from 233 patients-66 (94%) of 70 radical prostatectomies, 132 (89%) of 148 prostate needle biopsies, and 14 (93%) of 15 metastases-did not. In tumors in which the adenocarcinoma cells were positive, the staining intensity was weak and occurred in less than 1% of the cells. Tumors that stained positive for p63 were more likely to be high grade than those that did not (P <0.0001). Basal cells in PIA expressed p63, but these cells were sparsely distributed relative to the basal cells in the normal glands. Luminal cells in PIA were, in general, negative for p63. CONCLUSIONS: In contrast to normal and preneoplastic prostatic tissue, the vast majority of prostate adenocarcinomas do not express p63. Therefore, p63 immunohistochemistry represents a potential novel adjuvant method for facilitating the pathologic diagnosis of prostate cancer in prostate needle biopsies. The selective expression of p63 in normal basal cells, coupled with the finding that p63 null mice fail to develop prostates, provides strong evidence that the basal cells represent prostatic epithelial stem cells. In addition, these findings suggest that p63 may protect prostatic epithelial cells against neoplastic transformation and support the hypothesis that intermediately differentiated cells in the luminal epithelium of PIA are the targets of neoplastic transformation in the prostate.

GSTA1 expression in normal, preneoplastic, and neoplastic human prostate tissue.

BACKGROUND: Glutathione S-transferases (GSTs), inducible enzymes that catalyze the detoxification of reactive electrophiles and oxidants, protect against neoplastic transformation. Prostatic adenocarcinoma and high-grade prostatic intraepithelial neoplasia (HGPIN) fail to express GSTP1, a major class of GST. This failure of expression is associated with methlyation of the GSTP1 promoter, a somatic alteration proposed to be a critical step in prostatic carcinogenesis. However, simple atrophy and post-atrophic hyperplasia-proliferative lesions associated with chronic inflammation, which we have termed "proliferative inflammatory atrophy" (PIA)-express elevated levels of GSTP1. We postulated that this increase in GSTP1 expression in PIA occurs in response to increased oxidative stress. We examined the expression of another major class of GST, GSTA1, in the human prostate. METHODS: We performed immunohistochemistry against GSTA1 on formalin-fixed radical prostatectomies (n = 45). A stereological grid point counting method was used to estimate the percent of cells staining positive for GSTA1 in normal prostate, PIA, HGPIN, and adenocarcinoma. RESULTS: In contrast to GSTP1, normal peripheral zone epithelium was virtually devoid of GSTA1. Strikingly, though, epithelial cells in PIA demonstrated strong staining for GSTA1 (median of percent of cells staining positive = 44) as compared to those in normal peripheral zone (median = 3.0, P <.00001), HGPIN (median = 2.9, P <.00001), and adenocarcinoma (median = 3.8, P <.00001). Variations in GSTA1 were also detected between normal anatomic zones: the central zone showed an increase in the percentage of cells staining positive (median = 20.9) as compared to the transition (median = 0.47, P <.0002) and the peripheral (P <.0001) zones. CONCLUSIONS: Expression of GSTA1 is increased in PIA, supporting the concept that cells within these lesions are subject to localized increases in oxidative stress. Low levels of GSTA1 and GSTP1 in HGPIN and adenocarcinoma suggest a broad lack of detoxification activity in these cells, which may be associated with carcinogenesis in the prostate.

Renal artery pseudoaneurysm occurring after partial nephrectomy.

Retroperitoneal hemorrhage resulting from intrarenal pseudoaneurysm formation has been reported after percutaneous renal surgery. However, although hemorrhage is a well-recognized complication of partial nephrectomy, hemorrhage caused by an intrarenal pseudoaneurysm after open partial nephrectomy is rare. We report a case of retroperitoneal hematoma associated with a renal artery pseudoaneurysm occurring in a 56-year-old woman 2.5 weeks after she underwent left partial nephrectomy for renal cell carcinoma. The pseudoaneurysmal branch was successfully identified and selectively embolized using percutaneous renal arterial angiography.

Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome.

OBJECTIVES: To examine populations with diagnosed clinical interstitial cystitis (IC) and urethral syndrome and normal controls using the potassium sensitivity test (PST), to determine the incidence of PST-provoked pain and/or urgency, and to document the type and location of IC and urethral syndrome pain, association of pain with sexual intercourse, and family history of female urgency/frequency problems. METHODS: The PST and a questionnaire were administered to 466 patients with clinical IC, 116 patients with urethral syndrome, and 42 controls. RESULTS: The PST was positive in 78% of patients with clinical IC, in 55% of patients with urethral syndrome, and in 0% of the controls. Of the patients with clinical IC, 9% responded to the PST with pain only and 8% with urgency only. Patients with clinical IC reported the pain as dysuria (58%), urethral/vaginal (76%), above the pubic bone (53%), lower abdomen (47%), lower back (35%), vaginal (51%), and inguinal (28%). The results were similar for patients with urethral syndrome. Of the sexually active men and women, 71% with clinical IC and 59% with urethral syndrome reported pain associated with intercourse. Urgency/frequency problems in female relatives were reported by 35% of patients with IC and 33% of those with urethral syndrome. CONCLUSIONS: The significant potassium sensitivity in both patients with clinical IC and those with urethral syndrome and the absence of potassium sensitivity in normal controls indicates that a positive PST suggests the presence of an abnormal bladder epithelium. The lower rate of positive PSTs in patients with urethral syndrome reflects the less severe, more intermittent, nature of the symptoms in urethral syndrome (early IC). Pelvic pain of bladder origin may occur anywhere in the pelvis. Finally, IC appears to have a genetic component.